A Polymorphism Within the G6PC2 Gene Is Associated with Fasting Plasma Glucose Levels

• DOI: 10.1126/science.1156849
• Publication Date: 2008-05-04T04:48:51Z
• Authors: Nabila Bouatia-Naji; Ghislain Rocheleau; Leentje Van Lommel; Katleen Lemaire; Frans Schuit; Christine Cavalca...; Marion Marchand; Anna-Liisa Hartik...; Ulla Sovio; Franck De Graeve; Johan Rung; Martine Vaxillaire; Jean Tichet; Michel Marre; Beverley Balkau; Jacques Weill; Paul Elliott; Marjo-Riitta Jarv...; David Meyre; Constantin Polych...; Christian Dina; Robert Sladek; Philippe Froguel
• Keywords: Blood Glucose; Male; population; Polymorphism, Single Nucleotide; Body Mass Index; regulatory protein; 03 medical and health sciences; Meta-Analysis as Topic; Insulin-Secreting Cells; Insulin Secretion; Humans; Insulin; Genetic Predisposition to Disease; Alleles; disease; locus; 0303 health sciences; Fasting; Introns; Diabetes Mellitus, Type 2; genome-wide association; Glucose-6-Phosphatase; Linear Models; mortality risk; Female; diabetes-mellitus

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 × 10 –7 ) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit–related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient β = –0.06 millimoles per liter per A allele, combined P = 4 × 10 –23 ) and with pancreatic β cell function (Homa-B model, combined P = 3 × 10 –13 ) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic β cells.